5-heterocyclic amino derivatives of benzophenoxazine



Patented May 4, 1954 S-HETEROCYCLIC AMINO DERIVATIVES OFBENZOPHENOXAZINE Moses L. 'Crossley, Plainfield, Corris M. Hofmann,

Bound Brook, and Paul F. Dreisbach, Somerville, N. J., assignors toAmerican Cyanamid Company, New York, N. Y., a corporation of Maine NoDrawing. Application February 23, 1952, Serial No. 273,154

11 Claims. 1

This invention relates to a new series of dyes which are 5-heterocyclicamino substituted benzophenoxazines, and is a continuation-in-part ofcopending application Serial No. 100,092 filed June 18, 1949, nowabandoned.

The present invention is directed to a new group of dyestufis which, inthe form of their salts, range from blue to green, the free bases givingreddish colors in alcohol solution. The type formula of the new seriesin the form of its salts is as follows:

probable:

N- NR in which R is an aromatic heterocyclic radical and R1 and R2 arehydrogen or aliphatic radicals. Most of the members of the new series,however, are obtained more easily in the form of their salts in acidsolution. These salts are addition salts with 'strong mineral acids,such as nitric, hydrochloric, hydrobromic, and the like. In most uses,the particular anion is immaterial, as the characteristics of thecompound are determined primarily by the cation. Therefore, in practicaluse the nitrates or hydrochlorides are usually prepared, as these saltsare the simplest and cheapest to make. It should be understood, however,that the invention is not limited to the hydrochlorides and nitrates,and the other salts are included.

In the specification and claims, the heterocyclic radical B may bedefined as an unsaturated heterocyclic ring in which the bond from the5-position of the benzophenoxazine ring is attached through the aminonitrogen to a nuclear carbon atom of the heterocyclic radical. Theheterocyclic radical may contain nitrogen as its only heterocyclicelement, for example, pyridine, pyrimidine, pyrazine, imidazol,quinoxaline, quinoline, pyrazole, isopyrazole, pyrrole, isoimidazol,pyridazine, etc., or the heterocyclic ring may contain sulfur inaddition to nitrogen, for example, thiazole, benzothiazole, isothiazole,thiazine, thiadiazine, etc. Those compounds, the heterocyclic ring ofwhich contain sulfur, are claimed in copending application, Serial No.334,975, filed February 3, 1953.

The aliphatic amino group in the 9-position may be either amonoaliphatic or dialiphatic amino group. Among the most importantdyestuiis are those in which the aliphatic group is a lower alkyl group,such as methyl, ethyl, propyl, isopropyl, butyl, sec. butyl, etc. Otheralkyl groups, such as amyl, octyl, dodecyl or octadccyl may be attachedto the Q-arnino nitrogen as well as alkylene groups such as allyl,methallyl, oleyl, etc. In this specification and in the claims, the termaliphatic amino group will define a radical having the structure:

wherein R1 is an aliphatic hydrocarbon chain and R2 is either analiphatic hydrocarbon chain or hydrogen.

The products of the present invention are useful as dyestuffs andbiological stains and some of the membersare active against certainbacteria, such as mycobacteria.

The products of the present invention may be produced by variousprocesses, and it is not intended to limit them to any particularprocess of preparation. However, we have found that a very desirableprocess involves the reaction of an amino heterocyclic compound with a9-dialkylaminobenzoEalphenoxazonium salt, such as a chloride, nitrate,etc. In a more specific aspect of the present invention, this process isincluded.

For many staining uses, an alcoholic solution of the dyetufi is used,and in such cases it is frequently not necessary to isolate the purifiedproduct as a solid. When the dyestufis are to be used in the form ofsolutions, a considerable saving in cost results with certain memberswhich are difiicult to obtain in the form of a pure solid withoutconsiderable losses of material. Substantial cost savings may thus berealized in many cases.

The invention will be described in greater detail in conjunction withthe following specific examples. The parts are by weight.

EXAMPLE 1 5- (2'-pyridylamino) -9-dimethylaminobeneo[al phenoxazoniumchloride 169 parts of Q-dimethylaminobenzo[alphenoxazonium nitrate isdissolved in 1250 parts of ethyl alcohol with gentle warming. Themixture is then cooled to room temperature, and 141 parts of2-aminopyridine added. The mixture, which originally was reddish bluecolor, changes to a greenish blue, and after stirring until the reactionappears completed, the mixture is allowed to stand overnight. A blacksolid separates and is recovered by filtration. The precipitate is thenslurried in 1500 parts of ethanol and 100 parts of ammonium hydroxideadded. The nitrate salt is converted into the free base, which separatesas a reddish blue solid. The mixture is filtered, and the solidrecovered. The precipitate is then slurried in 500 parts of ethanol,warmed gently, and treated with ten parts of 12 N, hydrochloric acid.The reddish blue color of the mixture changes to a deep greenish blue,and the chloride separates out as a black solid, which is filtered,washed with a small amount of ethanol and dried.

The dyestuff in faintly ammoniacal ethanol solution shows a maximumabsorption of 531 m The maximum absorption of the acid ethanol solutionis at 670 m EXAMPLE 2 5 (2-pyridylamino) -9-diethylaminobenzo [a]phenorazonium chloride z ahN 183 parts ofQ-diethylaminobenzo[alphenoxazonium nitrate is dissolved in 1250 partsof ethanol, with gentle warming. The mixture is then cooled to 38 C.,and 141 parts of Z-aminopyridine are added. The solution changes from ared blue color to a deep blue. It is stirred occasionally until reactionappears complete and then allowed to stand overnight at roomtemperature. A super-saturated solution is produced, from which a solidprecipitate is obtained in the usual manner. It is recovered byfiltration as a shiny green solid. The precipitate is then slurried in1000 parts of ethanol and 100 parts of ammonium hydroxide solutionadded. The mixture changes to a deep red color, and the solid isrecovered by filtration.

The red solid is dissolved in 300 parts of glacial acetic acid and 87parts of ethanol, saturated with hydrogen chloride, is added. Thechloride of the dyestuff is precipitated by adding 1000 parts of diethylether and is recovered by filtra- EXAMPLE 3 5 (2-thiaeolylamino)-9-diethylaminobenzo [alphenomazonium chloride 183 parts ofQ-diethylaminobenzo[alphenoxazonium nitrate is dissolved in 1250 partsof ethanol by gentle warming, cooled to slightly above room temperature,and 150 parts of 2- aminothiazole added. The solution gradually changesfrom a red blue color to a deep green blue color. It is stirredoccasionally until reaction appears complete and is then allowed tostand overnight. A dark green solid precipitates which is recovered byfiltration, slurried in 150 parts of warm ethanol and treated with 10parts of ammonium hydroxide. The mixture changes to a deep red color andthe solid is recovered by filtration. The precipitate is then slurriedin 50 parts of warm ethanol and one part of 12 N. hydrochloric acidadded. The chloride separates out as a dark green solid, is recovered byfiltration and dried at 55 C.

If it is desired to purify the chloride obtained, it may be dissolved in100 parts of hot aqueous alcoholic hydrochloric acid having thecomposition of one part water, one part alcohol and two parts of 12 N.hydrochloric acid.

The maximum absorption of a faintly ammoniacal ethanol solution of thedyestuff is at 572 mu.

EXAMPLE 4 5 (2-pyrimidylamino) -9-diethylaminobcneo [a] phenorazine Theprocedure of Example 3 is followed, substituting 14.3 parts of2-aminopyrimidine for the 15 parts of 2-aminothiazole. The base obtainedfrom the ammoniacal alcoholic slurry is recrystallized from hot ethanol,the purified product being obtained in the form of very dark needleshaving a green cast.

The maximum absorption of a faintly ammoniacal ethanol solution of thedyestuff is at 550 m and that of a weakly acidic ethanol solution at 668111 4.

EXAMPLE 5 5 (2'-pyraeinylamino) -9-diethylaminobenzo [alphenorazom'umchloride a \O (N) The procedure of Example 3 is followed, re-

placing the aminothiazole with 143 parts of 2- aminopyrazine. The freebase is obtained as a deep red mixture, and on slurrying with 1000 partsof ethanol and 50 parts of concentrated hydrochloric acid the chlorideis precipitated.

Further purification can be effected by again converting the chloride tothe base with ammonium hydroxide and filtering, the base being much lesssoluble than the chloride and constituting a red black solid. Onehundred parts of this purified dried base is then converted to thechloride by heating in 7000 parts of ethanol, to which 400 parts ofethanol saturated with hydrogen chloride have been added. The mixture isfiltered hot and on cooling the chloride separates out as greencrystals. They may be dried at 100 C. Alcohol and water solutions aredeep blue in color, ammoniacal solutions red.

EXAIWPLE 6 [2' (4' 6'-dimethylpyrimidyl) amino] -9-diethylaminobeneo [a]phenor'azonium chloride 183 parts of Q-diethylaminobenzo[alphenoxazoniumnitrate is dissolved by warming in 1250 parts of ethanol. Two hundredparts of Z-aminolfi-dimethylpyrirnidine is added, the solution refiuxedfor about an hour and allowed to stand at room temperature for severaldays. A black solid precipitates out and is recovered by filtration. Theprecipitate is then slurried in 500 parts of ethanol and treated with100- parts of ammonium hydroxide. A dark red solid base pheoipitates outand can be converted into the chloride by slurrying in 300 parts ofethanol containing 50 parts of concentrated hydrochloric acid. Thechloride is a dark blue black solid.

The chloride of the dyestufi dissolves in alcohol or water to give anintensely blue solution. The addition of ammonia changes the color tored.

EXAMPLE 7 183 parts of. Q-diethylaminobenzo[alphenoxazonium nitratedissolved in 1250 parts of ethanol with gentle Warming. 194 parts of5-chloro- 2-aminopyrimidine is added and the solution allowed to standuntil the reaction mixture changes into a thick mass. The mixture isthen filtered and the precipitate slurried in 1000 parts of ethanolcontaining 100 parts of an ammonium hydroxide solution. A dark coloredsolid base precipitates, is recovered by filtration and transformedintothe chloride by slurrying with 1000 parts of ethanol containing 50parts of concentrated hydrochloric acid. The black solid produced isfiltered and dried.

The product is not quite pure and is purified by boiling in water andfiltering. The filtrate.

EXAMPLE 8 5[2'(4 methylpyrimidyl) amino] 9 cliethylaminobeneo [a]phlenorazom'um chloride 183 parts of Q-diethylaminobenzo[alphenoxazoniumnitrate is dissolved by warming in 1500 parts of ethanol. 164 parts ofZ-amino--methyl pyrimidine is added and the solution allowed to stand atroom temperature for several days. A black solid precipitates out, whichis recovered by filtration and is slurried in 500 parts of ethanol with50 parts of ammonium hydroxide. The mixture is boiled for a short periodof time, cooled and filtered, the base being obtained as a dark redsolid. It can be transformed into the chloride by slurrying in 500 partsof ethanol containing 50 parts of concentrated hydrochloric acid. Thechloride separates as a nearly black solid, which forms a deep bluesolution in alcohol, turning to red when ammonia is added.

EXAMPLE 9 5 (2' quinolylamz'no) 9 diethylaminobeneo- [alphenoraezne base18 parts of Q-diethylaminobenzo[alphenoxazonium nitrate is dissolved in130 parts of ethanol, then 22 parts of 2-aminoquinoline is added and thesolution is allowed to stand several hours. A green crystalline productseparates. This green product is collected and converted to the base bywarming in parts of ethanol and 10 parts ammonium hydroxide solution,then cooling the mixture and isolating the crystalline base byfiltration. This base dissolves in alcohol, giving a red solution whichis changed to a green-blue color by adding hydrochloric acid. 16 partsof the base are obtained.

EXAMPLE 10 5 (3' quinolylcmino) 9 diethylaminobenzo [a1phenoxaeoniumchloride 18 parts of 9-diethylaminobenzo[alphenoxazonium nitrate isdissolved in 130 parts of ethanol, and then a solution containing 22parts of 3-aminoquinoline dissolved in 200 parts of ethyl ethanol isadded. This latter solution is prepared by adding 8 parts of sodiummethylate to a warm mixture of 27 parts of 3-aminoquinolinehydrochloride in 200 parts of ethanol and filtering to remove the salt.

After the reaction mixture has stood for several days, it is filteredand the red-brown solid is slurried in 200 parts of water and 100 partsof ammonium hydroxide solution, and boiled. The mixture is filtered hot,and the black solid is then boiled in alcoholic ammonium hydroxide toinsure complete conversion to the base. The base is then converted tothe chloride by warming it in ethanol containing some concentratedhydrochloric acid. The mixture is cooled and filtered to isolate thechloride salt. This salt dissolves in alcohol, giving a blue solutionwhich changes to red by adding ammonium hydroxide, and back to blue byadding hydrochloric acid.

EXAMPLE 11 (4-quinolylamino) -9-diethylaminobenzo- [alphenorazomumchtoride 18 parts of Q-diethylaminobenzo [alphenox- 'azonium nitrate isdissolved in 130 parts of ethanol, and then 22 parts of -aminoquinolineis added. The solution is boiled for a few minutes and then allowed tostand at room temperature for several days. The mixture is filtered, andthe black solid is converted to the base by warming in 100 parts ofethanol with 10 parts of ammonium hydroxide solution. Conversion of thebase to the chloride is done by treating the black solid base withalcoholic hydrochloric acid.

The salt dissolves in alcohol giving a blue solution, which is changedto red by adding ammonium hydroxide solution.

EXAMPLE 12 The procedure of Example 1 is followed, replacing thedimcthylaminobenzo[alphenoxazonium nitrate with a correspondingdipropylamino compound. The product obtained is a greenish black solidin the form of its chloride and is transformed into a red base ontreatment with ammoniacal ethanol.

EXAMPLE 13 The procedure of Example 7 is followed, but thediethylaminobenzo [alphenoxazonium nitrate is replaced by thecorresponding dibutylamino compound. The dyestufi" obtained in the formof its free base is a reddish solid which dissolves in ammoniacalalcohol to form a red solution. 0n acidification with hydrochloric acidthe color is changed to a deep blue.

8 EXAMPLE 14 Q-di-n-butylmninobcnzo [a] phenoxazonium 792 parts of betanaphthcl, 5000 parts of ethyl alcohol and 115 parts of zinc chloride arerefluxed together in a suitable reaction vessel. Then 1490 parts ofp-nitroso di-n-butylaniline is added to the hot solution in smallportions over a period of one hour. The reaction solution goes through acolor change and finally becomes a purple color, with a. crystallineproduct separating. The mixture is refluxed one hour longer and filteredhot, and the dark crystalline product is washed on the funnel with hotalcohol and then dried. This product (078 parts) is the ch1oride-zincchloride double salt, which is converted to the nitrate salt bydissolving in 12 liters of boiling water, filtering the hot solution,cooling the filtrate and adding 6360 parts of (sp. gr. 1.42) nitricacid. The nitrate salt separates as a black solid in a nearlyquantitative yield. The product is isolated by filtration, and dried inthe air.

EXAMPLE 15 5 2 -pyridylami'no) -9-di-n-butylaminobenzo- [a]phenoztazonium nitrate 211 parts ofQ-di-n-butylaminobenzo[alphenoxazoniurn nitrate is dissolved in 1000parts of warm ethyl alcohol, then 141 parts of 2-aminopyridine is addedand the solution is warmed on a steam bath for 5 minutes. The color ofthe solution changes from a reddish-blue to a greenish-blue. Afterstanding for several days at room temperature, the mixture is filteredand the green metallic crystalline product is dried. There is obtained163 parts of crude product, which is recrystallized from 8000 parts ofhot alcohol giving 137 parts of purified material. This productdissolves in alcohol, giving a blue solution, which changes to red bythe addition of ammonia, and back to blue by the addition ofhydrochloric acid.

EXAMPLE 16 5- (2'-pyrimtdylamino) -9-di-n-butylaminobenzo [a]p'hcnoxazonium nitrate 211 parts of9-di-n-butylaminobenzo[alphenoxazonium nitrate is dissolved in 1000parts of warm ethyl alcohol, then 143 parts of Z-aminopyrimidine isadded and the solution is warmed on a steam bath for 5 minutes. Thecolor of the solution changes from a reddish-blue to a greenish-blue.After standing for several days at room temperature, the thick mixtureis fil EXAMPLE 17 Q-di-n-propylaminobenzo[a]phenoxazonium nitrate(CaHDzITT This is prepared in the same manner asB-di-nbutylaminobenzo[al-phenoxazonium nitrate, Substituting p-nitrosodi-n-propylam'line in this case for the p-nitroso di-n-butylaniline.

EXAMPLE 18 2 -pgrz'dylamino) -9di-n-propytaminobenzoalphenoraeoniumnitrate 47 parts of 9-di-n-propylaminobenzo[alphenoxazonium nitrate isdissolved in 250 parts of warm ethyl alcohol and then 34 parts of2-aminopyridine is added, and the solution is warmed on the steam bathfor 5 minutes. After standing at room temperature for several days, themixture is filtered and the metallic green product is dried. There isobtained 44 parts of crude product which can be purified from 2000 partsof hot alcohol to give 33 parts of purified material. This green solidproduct dissolves in alcohol giving a blue solution, which changes tored by the addition of ammonia and back to blue by the addition ofhydrochloric acid.

EXAMPLE 19 9 cliethylamino 11 methylbenzoialphenoxaaonzum nitrate CzHs)21? 0 during the addition of the nitroso. After the nitroso compound hasbeen added, the purple mixture is stirred one-half hour, filtered hotand the dark crystalline product is Washed on the funnel with warmalcohol. There is obtained 718 parts of zinc chloride double salt whichis converted to the nitrate salt by dissolving 600 parts of the zincchloride salt in 40,000 parts of hot water, clarifying, cooling thefiltrate and adding 2130 parts of nitric acid (sp. gr. 1.42). Thenitrate separates as a nearly black solid.

There is obtained, after filtering and drying, 54? parts of the nitratesalt.

EXAMPLE 20 114 parts of 9-diethylamino-ll-methylbenzo- [alphenoxazoniumnitrate is dissolved in 1250 parts of warm ethyl alcohol, then 90 partsof 2-aminothiazole is added and the solution is warmed on a steam bathfor a few minutes. The color changes from a reddish-blue to agreenish-blue. After standing a few hours, a thick mass forms, which isallowed to stand at room temperature for several hours to complete thereaction. By filtration the product is obtained as a green solid (46parts) which can be purified by crystallization from 500 parts of hotethyl alcohol to give 34 parts of the product as a brown solid. Thissolid dissolves in alcohol giving a purple solution which changes toyellow by adding ammonia and back to purple by adding hydrochloric acid.

EXAMPLE 21 I i i A solution of 132 parts of the zinc chloride(HOCHzCHQElT' double salt of 9bis-(beta-hydroyethyl)amino-'benzo[alphenoxazonium chloride, parts of 2- aminopyridine and 1000parts of ethyl alcohol is warmed on a steam bath for 10 minutes. Thecolor changes from deep red-blue to a greenblue. The solution is allowedto stand at room temperature about 24'hours, after which time some ofthe alcohol has evaporated and a dark colored oil has separated. Severalvolumes of water are added, with stirring, to solidfy the oil. Themixture is filtered, and the dark brown solid product is washed withwater and then dried. About 152 parts of crude product is obtained whichcan be recrystallized from a large volume of hot alcohol. The purifiedproduct in acidified alcohol gives a blue solution which changes to redby addition of ammonia. An alcohol solution of this material showsmaximum absorption peaks'atwave lengths of 534 millimicrons and 680millimicrons on the acidic and basic sides, respectively.

EXAMPLE 22 5 (2 benzothiazolg/lamino) 9 dz n propylamznobenzo [a]phenoxaeonium nitrate CaH7 To 4.7 parts of 9-di-n-propylaminobenzo[a]-phenoxazonium nitrate, prepared as described in Example 1'7, are added25 parts of ethyl alcohol and 5.4 parts of Z-aminobenzothiazole. Themixture is warmed gently for a few minutes to effect solution. Afterstirring, the solution is allowed to EXAMPLE 23 5 (2benzimidaeolylamino) 9 di-n-propylaminobenzolalphenoxazonium nitrate To4.7 parts of Q-di-n-propylaminobenzo[alphenoxazonium nitrate, preparedas described in Example 17, are added 25 parts of ethyl alcohol and 4.8parts of Z-aminobenzimidazole. mixture is warmed gently until a solutionis obtained. The solution is allowed to stand for several days at roomtemperature in an open vessel and the solid which precipitates isremoved by filtration and purified by treatment with ethyl alcohol.

The purified dark solid obtained in this way forms a blue solution inethyl alcohol, changing to red by the addition of an alkaline reagent.An acidified alcohol solution of this product shows absorption in the660 to 640 m range. An alkaline alcohol solution of this solid showsmaximum absorption in the 570 to 590 m i range.

We claim:

1. Compounds having the formula:

X- NR in which X is an N aliphatic hydrocarbon amino group of not morethan 18 carbon atoms; Y is a The I 12 substituent selected from thegroup consisting of hydrogen and lower alkyl radicals; and R is aheterocyclic radical, the heterocyclic ring of which contains nitrogenas its only heterocyclic element; and their acid addition salts.

2. The acid addition salt of a base having the bk I in which X is an Naliphatic hydrocarbon amino group of not more than 18 carbon atoms.

3. The acid addition salt of a base having the formula:

in which X is an N aliphatic hydrocarbon amino group of not more than 18carbon atoms.

4. The acid addition salt of a base having the formula I l N X \o KN} inwhich X is an N aliphatic hydrocarbon amino group of not more than 18carbon atoms.

5. The acid addition salt of a base having the formula:

in which X is an N aliphatic hydrocarbon amino group of not more than 18carbon atoms.

6. The acid addition salt of a base having the formula:

in which X is an N aliphatic hydrocarbon amino group of not more than 18carbon atoms.

7. Compounds having the following formula:

13 14 8. Compounds having the following formula: 11. Compounds haoingthe following formula:

cmnpwnds having the mrmula References Cited in the file of this patentUNITED STATES PATENTS Number Name Date N\ 2,528,862 Crossley et a1. Nov.7, 1950 C H 15 2,528,863 Crossley et a1. Nov. '7, 1950 l 9 FOREIGNPATENTS 0 1 Number Country Date H 488,945 Germany Jan. 25, 1930 10.Compounds havmg the following formul 20 556,773 France Apr, 19, 1923630,707 France Aug. 2'7, 1927 OTHER REFERENCES /N\ Sloviter: J. Am.Chem. 800., vol. '71, pp. 3360-2 25 (1949). CzHl \N N 0 1 \N

1. COMPOUNDS HAVING THE FORMULA: